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The stapled peptide PM2 stabilizes p53 levels and radiosensitizes wild-type p53 cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Marika Nestor)ORCID iD: 0000-0002-6771-3289
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.ORCID iD: 0000-0002-1509-2142
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(English)Manuscript (preprint) (Other academic)
Keywords [en]
p53, wt p53 cancers, radiosensitization, external beam radiotherapy, PM2
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-341769OAI: oai:DiVA.org:uu-341769DiVA, id: diva2:1182768
Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2018-02-18
In thesis
1. Precision medicine and targeted therapy: Turning the tables on cancer
Open this publication in new window or tab >>Precision medicine and targeted therapy: Turning the tables on cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An extended understanding of the molecular characteristics of cancer has led to a revolution within the field of precision medicine. This thesis explores the utilization of two targets for precision medicine, namely, CD44v6 and murine double-minute 2 and X (MDM2/X).

A novel mini-antibody construct targeting CD44v6 (AbD19384), was assessed for possible use in radiodiagnostics, while a recombinant full-length anti-CD44v6 antibody based on the same construct, AbN44v6, was evaluated for radio-immunotherapy (RIT) following labeling with 177Lu and 131I. Additionally, normal tissue biodistribution and dosimetry was assessed for radiolabeled AbN44v6. The efficacy and mechanisms behind the observed effects of PM2 therapy, a novel stapled peptide that inhibits MDM2/X, were assessed in vitro and in vivo both as monotherapy and in combination with external beam radiotherapy (EBRT). Lastly, combination therapy using RIT (177Lu-AbN44v6) and PM2 was evaluated in an in vitro 3D tumor spheroid model.

AbD19384 successfully visualized CD44v6-positive xenografts. Similarly, radiolabeled AbN44v6 bound specifically to CD44v6, and RIT resulted in antigen-dependent, activity-dependent growth inhibition of in vitro 3D tumor spheroids. Biodistribution and dosimetry revealed low-level accumulation in normal tissues and low total effective doses of 0.1 mSv/MBq of injected radioconjugate. PM2-based therapy increased pro-apoptotic protein levels and caused growth inhibition of wt p53 cancer cell lines, which was amplified in combination with radiotherapy. In vivo studies of wt p53 and p53-knockout xenografts demonstrated the specificity of PM2 towards wt p53 cancers and established the potency of combining PM2-based therapy with EBRT.

The work presented in this thesis exemplifies the potency of combination treatments based on a precise understanding of the targeted cancer. Utilizing not one but several of the molecular characteristics of a specific cancer will help turn the tables on cancer and improve patient outcomes in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1430
Keywords
p53 cancers, PM2, radiosensitization, radio-immunotherapy, MDM2/X inhibition, combination therapy, targeted radionuclide therapy, CD44v6
National Category
Medical and Health Sciences
Research subject
Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-342030 (URN)978-91-513-0239-3 (ISBN)
Public defence
2018-04-06, Rudbecksalen, Dag Hammarskjölds Väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-03-13 Created: 2018-02-18 Last updated: 2018-04-24

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